1. Field of the Invention
This invention relates to 7,8,9,10-tetrahydro-2-hydroxy-3-substituted-dibenzo[b,d]pyrans, corresponding 6,7,8,9,10,10a-hexahydrodibenzo[b,d]pyrans, 5,6,7,8,9,10-hexahydro-2-hydroxy-3-substituted-benzo[c]quinolines, 5,6,6a,7,8,9,10,10a-octahydro-benzo[c]quinolines and derivatives thereof of the formula (I) and (II) all of which are useful as analgesics in mammals, including man. Some of the compounds of formula (I) and (II) are also useful as tranquilizers or diuretics in mammals, including man and as intermediates.
2. Description of the Prior Art
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesic agent such as d-propoxyphene, codeine, and morphine possess addictive liability. The need for improved and potent analgesic agents is, therefore, evident.
The CNS active dibenzo[b,d]pyrans disclosed in the prior art are 1-hydroxy-9-substituted compounds closely related in structure to the naturally occurring dibenzo[b,d]pyrans. See, for example, the following review articles: R, Mechoulam, Editor, "Marijuana, Chemistry, Pharmacology, Metabolism and Clinical Effects," Academic Press, New York, N.Y., 1973; Mechoulam, et. al., Chemical Reviews, 76, 75-112 (1976). In addition, rather comprehensive reviews are set forth in U.S. Pat. No. 3,886,184 and U.S. Pat. No. 3,968,125.
U.S. Pat. Nos. 3,507,885 and 3,363,058, issued Apr. 21, 1970 and Jan. 18, 1972, respectively, describe various 1-hydroxy-3-alkyl-6H-dibenzo[b,d]pyrans having at the 9-position substituents such as: oxo, hydrocarbyl and hydroxy or chloro, hydrocarbylidene, and intermediates therefor.
Hoops et al., J. Org. Chem., 33, 2995-2996 (1968) describe the preparation of the 5-aza analog of .DELTA..sup.6a(10A) -tetrahydrocannabinol referred to therein as 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3-n-pentylphenanthridine , but report no utility for the compound. Beil, in "Pyschomimetic Drugs", edited by Efron, Raven Press, New York, 1970, page 336, reports the compound was "completely inert in animal pharmacology."
Hardman et al., Proc. West. Pharmacol. Soc. 14, 14-20 (1971) reports some pharmacological activity for 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentyl phenanthridine, a 5-aza .DELTA..sup.6a(10a) -tetrahydrocannabinol.
The only known 2 -hydroxy-isomer of tetrahydrocannabinol is 6,7,8,9-tetrahydro-2-hydroxy-3-n-amyl-6,6,9-trimethyldibenzo[b,d]pyran prepared by Russell et al., J. Chem. Soc., 169 (1941). It was found to be inactive at does of 20 mg./kg. in rabbits.
Mechoulam and Edery in "Marijuana", edited by Mechoulam, Academic Press, New York, 1973 page 127, observe that major structural changes in the tetrahydrocannabinol molecule seem to result in steep reductions in anagesic activity.
Paton, In Annual Review of Pharmacology, 15, 192 (1975) presents generalizations on structure-action relationships among canabinoids. The presence of the gem dimethyl group in the pyran ring is critical for cannabinoid activity and substitution of N for O in the pyran ring removes activity.